Defective mammopoiesis, but normal hematopoiesis, in mice with a targeted disruption of the prolactin gene

Abstract

Prolactin (PRL) has been implicated in numerous physiological and developmental processes. The mouse PRL gene was disrupted by homologous recombination. The mutation caused infertility in female mice, but did not prevent female mice from manifesting spontaneous maternal behaviors. PRL-deficient males were fertile and produced offspring with normal Mendelian gender and genotype ratios when they were mated with heterozygous females. Mammary glands of mutant female mice developed a normal ductal tree, but the ducts failed to develop lobular decorations, which is a characteristic of the normal virgin adult mammary gland. The potential effect of PRL gene disruption on antigenindependent primary hematopoiesis was assessed. The results of this analysis indicated that myelopoiesis and primary lymphopoiesis were unaltered in the mutant mice. Consistent with these observations in PRL mutant mice, PRL failed to correct the bone marrow B cell deficiency of Snell dwarf mice. These results argue that PRL does not play any indispensable role in primary lymphocyte development and homeostasis, or in myeloid differentiation. The PRL -/-mouse model provides a new research tool with which to resolve a variety of questions regarding the involvement of both endocrine and paracrine sources of PRL in reproduction, lactogenesis, tumorigenesis and immunoregulation.

Prolactin gene-disruption arrests mammary gland development and retards T-antigen-induced tumor growth

“…We had previously shown that the mammary epithelium in PRL-de®cient mice was limited to a system of simple branched ducts. Normal (PRL +/7 ) glands, in contrast, developed an extensive ductal system decorated with ®ne branches and alveolar buds (Horseman et al, 1997). We con®rmed that qualitative observation here, and extended it by studying aged mice and hormonal rescue of the phenotype, and by quantifying branch densities in treatment groups.…”

“…In others, including the mixed Swiss Black/129Sv background used in these studies, the gland matures in the nulliparous mouse under the in¯uence of hormones during the estrous cycles. As reported by us previously (Horseman et al, 1997), extensive subordinate arborization and alveolar budding were observed in the glands of heterozygous (PRL +/7 ) mice ( Figure 1a). Ductal development was arrested in the mammary glands of PRL 7/7 mice, such that the gland consisted of a network of dichotomous branches with no subordinate branching or alveolar budding.…”

“…These PRL actions, along with possible activities in breast cancer (Ginsburg and Vonderhaar, 1995), provided an impetus to develop PRL gene-disrupted mice (Horseman et al, 1997). In this paper we have used several approaches to investigate PRL actions in mammary gland development and breast cancer.…”

“…We produced mice with a disruption of the PRL gene with the ultimate goal of gaining a better understanding of both normal mammary gland development and breast tumorigenesis (Horseman et al, 1997). Here we show additional details to characterize the control of mammary gland development in this mouse model, and compare the growth of oncogene-induced mammary tumors in normal and PRL gene-disrupted mice.…”

“…Experimental analysis of PRL actions in mouse mammary glands has been, of necessity, limited to studying either tissues from midpregnant animals or cells in culture that have been previously exposed to lactogens, and then withdrawn from hormonal stimulation. The mouse PRL gene was disrupted by homologous recombination (Horseman et al, 1997), and these animals provided an in vivo system in which pubertal mammary organogenesis proceeds in the absence of PRL from either pituitary or from extrapituitary sources. The arrested mammary gland development in PRL gene-disrupted mice is an experimental platform from which to study PRL-regulated events at their earliest stages.…”